Emerging Optical Methods for Endoscopic Barrett’s Surveillance

Barrett’s oesophagus is an acquired metaplastic condition that predisposes patients to the development of oesophageal adenocarcinoma, prompting the use of surveillance regimes to detect early malignancy for endoscopic therapy with curative intent. The currently accepted surveillance regime uses white light endoscopy together with random biopsies, but suffers poor sensitivity and discards information from numerous light-tissue interactions that could be exploited to probe structural, functional and molecular changes in the tissue. Advanced optical methods are now emerging that are exquisitely sensitive to these changes and hold significant potential to improve surveillance of Barrett’s oesophagus if they can be applied endoscopically. The next decade will see some of these exciting new methods applied to Barrett’s surveillance in new device architectures for the first time, potentially leading to a longawaited improvement of the standard of care

Increased toxin expression in a Clostridium difficile mfd mutant

BACKGROUND: The symptoms of Clostridium difficile infection are mediated primarily by two toxins, TcdA and TcdB, the expression of which is governed by a multitude of factors including nutrient availability, growth phase and cell stress. Several global regulators have been implicated in the regulation of toxin expression, such as CcpA and CodY. RESULTS: During attempts to insertionally inactivate a putative secondary cell wall polysaccharide synthesis gene, we obtained several mutants containing off-target insertions. One mutant displayed an unusual branched colony morphology and was investigated further. Marker recovery revealed an insertion in mfd, a gene encoding a transcription-coupled repair factor. The mfd mutant exhibited pleiotropic effects, in particular increased expression of both toxin A and B (TcdA and TcdB) compared to the parental strain. Western blotting and cellular cytotoxicity assays revealed increased expression across all time points over a 24 h period, with inactivation of mfd resulting in at least a 10 fold increase in cell cytotoxicity. qRT-PCR demonstrated the upregulation of both toxins occurred on a transcriptional level. All effects of the mfd mutation were complemented by a plasmid-encoded copy of mfd, showing the effects are not due to polar effects of the intron insertion or to second site mutations. CONCLUSIONS: This study adds Mfd to the repertoire of factors involved in regulation of toxin expression in Clostridium difficile. Mfd is known to remove RNA polymerase molecules from transcriptional sites where it has stalled due to repressor action, preventing transcriptional read through. The consistently high levels of toxin in the C. difficile mfd mutant indicate this process is inefficient leading to transcriptional de-repression

The UK Paediatric Familial Hypercholesterolaemia Register: Statin-related safety and 1-year growth data

BACKGROUND: For children with familial hypercholesterolemia (FH), UK guidelines recommend consideration of statin therapy by age 10 years and dietary and lifestyle advice to maintain an ideal body weight. OBJECTIVES: The objective of the study is to use the UK Paediatric Familial Hypercholesterolemia Register to determine: (1) the prevalence of plasma markers of liver toxicity and muscle damage in statin-treated FH children; (2) the prevalence of obesity in FH children compared to the UK general population; and (3) to compare growth rates in statin-treated and nontreated children. METHODS: Differences in registration and 1-year characteristics were compared by Mann-Whitney U tests. Age and gender body mass index percentiles were compared to UK children's growth charts. RESULTS: In 300 children (51% boys, 75% Caucasian, untreated mean [standard deviation] low-density lipoprotein cholesterol 5.50 [1.49] mmol/L), the proportion on statins varied significantly (P 15 years = 73.2%). Statin treatment reduced low-density lipoprotein cholesterol by 31% (1.84 [1.43] mmol/L), and no child showed elevated levels of markers of liver toxicity or muscle damage. At registration, 16.9% of the FH children were overweight (>85th percentile) and 11.1% were obese (>95th percentile) vs reported in 21.2% in UK non-FH children. There was no difference in annual growth rate in statin vs no-statin groups (age-adjusted weight increases 3.58 vs 3.53 kg; P = .91, height 4.45 vs 4.60 cm P = .73). CONCLUSIONS: We show no evidence for statin-related safety or growth issues, but many FH children over the age of 10 years are not on statin treatment. Fewer UK children with FH are obese compared to UK non-FH children

In Vitro Microvessel Growth and Remodeling within a Three-Dimensional Microfluidic Environment

This paper presents in vitro microvascular network formation within 3D gel scaffolds made from different concentrations of type-I collagen, fibrin, or a mixture of collagen and fibrin, using a simple microfluidic platform. Initially, microvascular network formation of human umbilical vein endothelial cells was examined using live time-lapse confocal microscopy every 90 min from 3 h to 12 h after seeding within three different concentrations of collagen gel scaffolds. Among the three collagen gel concentrations, the number of skeletons was consistently the highest at 3.0 mg/mL, followed by those of collagen gel scaffolds at 2.5 mg/mL and 2.0 mg/mL. Results demonstrated that concentration of collagen gel scaffolds, which influences matrix stiffness and ligand density, may affect microvascular network formation during the early stages of vasculogenesis. In addition, the maturation of microvascular networks in monoculture under different gel compositions within gel scaffolds (2.5 mg/mL) was examined for 7 days using live confocal microscopy. It was confirmed that pure fibrin gel scaffolds are preferable to collagen gel or collagen/fibrin combinations, significantly reducing matrix retractions during maturation of microvascular networks for 7 days. Finally, early steps in the maturation process of microvascular networks for 14 days were characterized by demonstrating sequential steps of branching, expanding, remodeling, pruning, and clear delineation of lumens within fibrin gel scaffolds. Our findings demonstrate an in vitro model for generating mature microvascular networks within 3D microfluidic fibrin gel scaffolds (2.5 mg/mL), and furthermore suggest the importance of gel concentration and composition in promoting the maturation of microvascular networks.Singapore-MIT Alliance for Research and Technolog

Current management of children and young people with heterozygous familial hypercholesterolaemia - HEART UK statement of care

This consensus statement on the management of children and young people with heterozygous familial hypercholesterolaemia (FH) addresses management of paediatric FH in the UK, identified by cascade testing when a parent is diagnosed with FH and for those diagnosed following incidental lipid tests. Lifestyle and dietary advice appropriate for children with FH; suggested low density lipoprotein cholesterol (LDL-C) targets and the most appropriate lipid-lowering therapies to achieve these are discussed in this statement of care. Based on the population prevalence of FH as ~1/250 and the UK paediatric population, there are approximately 50,000 FH children under 18 years. Currently only about 550 of these children and young people have been identified and are under paediatric care

Number word use in toddlerhood is associated with number recall performance at seven years of age

Previous studies have shown that verbal working memory and vocabulary acquisition are linked in early childhood. However, it is unclear whether acquisition of a narrow range of words during toddlerhood may be particularly related to recall of the same words later in life. Here we asked whether vocabulary acquisition of number words, location and quantifier terms over the first three years of life are associated with verbal and visuospatial working memory at seven years. Our results demonstrate that children who produced more number words between 20-26 months and started to produce the number words 1-10 earlier showed greater number recall at 7 years of age. This link was specific to numbers and neither extended to quantifier and location terms nor verbal and visuospatial working memory performance with other stimuli. These findings suggest a category-specific link between the mental lexicon of number words and working memory for numbers at an early age. © 2014 Libertus et al

Clinical and cost effectiveness of mechanical support for severe ankle sprains: design of a randomised controlled trial in the emergency department [ISRCTN 37807450]

Background The optimal management for severe sprains (Grades II and III) of the lateral ligament complex of the ankle is unclear. The aims of this randomised controlled trial are to estimate (1) the clinical effectiveness of three methods of providing mechanical support to the ankle (below knee cast, Aircast® brace and Bledsoe® boot) in comparison to Tubigrip®, and (2) to compare the cost of each strategy, including subsequent health care costs. Methods/design Six hundred and fifty people with a diagnosis of severe sprain are being identified through emergency departments. The study has been designed to complement routine practice in the emergency setting. Outcomes are recovery of mobility (primary outcome) and usual activity, residual symptoms and need for further medical, rehabilitation or surgical treatment. Parallel economic and qualitative studies are being conducted to aid interpretation of the results and to evaluate the cost-effectiveness of the interventions. Discussion This paper highlights the design, methods and operational aspects of a clinical trial of acute injury management in the emergency department

Imaging spontaneous currents in superconducting arrays of pi-junctions

Superconductors separated by a thin tunneling barrier exhibit the Josephson effect that allows charge transport at zero voltage, typically with no phase shift between the superconductors in the lowest energy state. Recently, Josephson junctions with ground state phase shifts of pi proposed by theory three decades ago have been demonstrated. In superconducting loops, pi-junctions cause spontaneous circulation of persistent currents in zero magnetic field, analogous to spin-1/2 systems. Here we image the spontaneous zero-field currents in superconducting networks of temperature-controlled pi-junctions with weakly ferromagnetic barriers using a scanning SQUID microscope. We find an onset of spontaneous supercurrents at the 0-pi transition temperature of the junctions Tpi = 3 K. We image the currents in non-uniformly frustrated arrays consisting of cells with even and odd numbers of pi-junctions. Such arrays are attractive model systems for studying the exotic phases of the 2D XY-model and achieving scalable adiabatic quantum computers.Comment: Pre-referee version. Accepted to Nature Physic

Timescales of Massive Human Entrainment

The past two decades have seen an upsurge of interest in the collective behaviors of complex systems composed of many agents entrained to each other and to external events. In this paper, we extend concepts of entrainment to the dynamics of human collective attention. We conducted a detailed investigation of the unfolding of human entrainment - as expressed by the content and patterns of hundreds of thousands of messages on Twitter - during the 2012 US presidential debates. By time locking these data sources, we quantify the impact of the unfolding debate on human attention. We show that collective social behavior covaries second-by-second to the interactional dynamics of the debates: A candidate speaking induces rapid increases in mentions of his name on social media and decreases in mentions of the other candidate. Moreover, interruptions by an interlocutor increase the attention received. We also highlight a distinct time scale for the impact of salient moments in the debate: Mentions in social media start within 5-10 seconds after the moment; peak at approximately one minute; and slowly decay in a consistent fashion across well-known events during the debates. Finally, we show that public attention after an initial burst slowly decays through the course of the debates. Thus we demonstrate that large-scale human entrainment may hold across a number of distinct scales, in an exquisitely time-locked fashion. The methods and results pave the way for careful study of the dynamics and mechanisms of large-scale human entrainment.Comment: 20 pages, 7 figures, 6 tables, 4 supplementary figures. 2nd version revised according to peer reviewers' comments: more detailed explanation of the methods, and grounding of the hypothese